Robust cleaning and disinfection programmes are needed to meet the required cleanroom microbial grades, to prevent cross contamination and subsequent microbial contamination of ­products. Incidents of contaminated product entering the supply chain with devastating consequences have happened in the last 8 years in the UK, USA, France, Italy, South Africa.

An inadequate microbial control programme can cause significant risk to patient safety, at the very least product recall, and financial loss to the company. Control of microbiological contamination and root-cause investigation are among the top 10 most observed deficiencies by the FDA since 2012. A similar situation is observable in Europe based on MHRA deficiencies reported.
The manufacture of both human and veterinary medicines in the EU is governed by EudraLex Vol 4 Good Manufacturing Practice — “The rules governing medicinal products in the European Union“. Each country in Europe takes this legislation into their own country specific legislation: Rules and Guidance for Pharmaceutical Manufacturers and Distributors (The Orange Guide) in the UK, Guide des Bonnes Pratiques de Fabrication (BPF) in France and GMP-Leitfaden zur “Guten Herstellungspraxis“ in Germany. Annex 1 of EU GMP specifically covers the Manufacture of Sterile Medicinal Products.

Annex 1 Manufacture of Sterile Medicinal Products
EU Annex 1 which specifies guidance for the manufacture of sterile medicinal products was first issued in 1989, revised in 1996 with partial updates in 2003 and 2007. With no complete review of the annex having been carried out for over ten years, a complete review and rewrite was needed. The annex needed to catch up with both changes in sterile manufacturing technology (RABS, isolators, rapid microbiological methods) and significant updates in regulatory expectation, the introduction of ICH Q 9 for Quality Risk Management, ICH Q 10 which describes Pharmaceutical Quality Systems, and the changes regarding the production of Water for Injection to include methods other than distillation. Additionally, there were some areas of the current version of the annex which were ambiguous and needed correction or clarification. As Annex 1 has come to be used beyond sterile manufacturing, the scope of the new draft was also modified to reflect this.
A rewrite and not a revision was necessary, and in December 2017 the European Commission via a GMP/GDP working group produced a draft of Annex 1. The working group of 16 representatives included the Pharmaceutical Inspection Cooperation Scheme, (PIC/S), WHO and EMA, in total 52 authorities including the FDA, Japan, Australia, Canada, EDQM and ICH were involved.

document has been rewritten, the current 16-page document is replaced with a potential 50-page document. Each topic has been significantly expanded, new topics have been included and the concept of risk management is embedded throughout the document. Thousands of comments were returned from industry and industry groups in response to the draft. An updated draft was prepared by the then rapporteur Andrew Hopkins and sent to the drafting group. Andrew Hopkins has since left the MHRA and a new rapporteur (French inspector) has been identified. The IWG have been informed that industry wants a further consultation but there has been no decision so far. The general feeling is that Annex 1 will not be released anytime soon, poten­tially the end of 2019, but that even if changes are forthcoming the main ethos and the general direction of travel for the draft will remain the same.

General summary of changes
There are now 269 different clauses, increased from 100 in the current version. Many of these have been expanded on. There are some 100 clauses which contain no link to an existing clause, there are only 14 clauses in the current document which are not present in any form in the draft and just 40 clauses that are unchanged. The new sections include single use technologies, aseptic operator qualification, application of Quality Risk, disinfectant qualification for cleanroom surfaces, process water systems, including the manufacture of Water-for-Injection, other utilities and closed manufacturing systems.
One of the main documentary requirements of the new draft is the requirement for a holistic contamination control strategy (CCS).

Contamination Control Strategy
This document, either in one master document or separate related documents will reflect a site-wide strategy for minimising contamination. Whichever way is chosen, it must be a “living” document, which is kept up to date throughout the life cycle of the facility. CCS is mentioned 19 times in the draft, and some EU national agencies are already requesting a CCS. For established facilities it probably already exists even if across separate documents and the manufacturer should try to include links and references in order not to rewrite all qualification documents. New facilities should start the CCS as early in the process as possible, it should ideally form part of the design process and be included in URS and DQ documents.
The draft states that “A contamination control strategy should be implemented across the facility in order to assess the effectiveness of all the control and monitoring measures employed. This assessment should lead to corrective and preventative actions being taken as necessary. The strategy should consider all aspects of contamination control and its life cycle with on going periodic review and update of the strategy as appropriate.”
The main elements will include:

• Design of plant and process
• Equipment and facilities
• Personnel
• Utilities
• Raw material control
• Product containers and closures
• Vendor approval
• Process risk management
• Process validation
• Preventative maintenance
• Cleaning and disinfection
• Monitoring systems
• Prevention-trending, investigations CAPA
• Continuous improvement.

Cleaning and disinfection
The references to cleaning and disinfection have been expanded. The word disinfection has been used to replace sanitation as the title of the section. The terminology of “cleaning” has been replaced with “cleaning and disinfection”. The text notes that “for disinfection to be effective, cleaning to remove surface contamination must be performed first”. This clarifies current best practice that cleaning and disinfection are two distinct activities trying to achieve different things. Cleaning is the removal of non-viable contamination by physical means or by suitable agents to render a surface visibly clean. The draft annex defines disinfection as “the process by which surface bioburden is reduced to a safe level or eliminated. Some disinfection agents are effective only against vegetative microbes, while other possess additional capability to effectively kill bacterial and fungal spores.”

Many common and well used disinfectants, for example amines, amphoterics and quaternary ammonium compounds leave significant residues on a surface, which can subsequently have a detrimental effect on the effectiveness of the disinfectant used. This is acknowledged in the new draft, “Cleaning programs should be effective in the removal of disinfectant residues.” There are disinfectants available which do leave minimal to no residue, or which have residues which are free rinsing or easily removable. The draft annex states that the cleaning process should be validated so that it can be demonstrated that it can remove any residue that would create a barrier between the sterilizing agent and the equipment surface. (NB the use of the word sterilizing here has been challenged during the consultation period.) The validation should also prove that residues are removed that could contaminate the product with either chemical or particulate contamination.

Rotation
Regulatory guidelines are currently not aligned on the subjection of rotation and the number of disinfectants which need to be used. The US FDA, Japan and ANVISA don’t specify and expect it to be based on a review of EM data. EU GMP Annex 1 previously stated that “more than one type of disinfecting agent should be employed” and this is repeated in the draft. In line with other regulatory guidance the phrase “….include the periodic use of a sporicidal agent ” has been added.

If the risk management approach of the rest of the guide is applied, the number and frequency of disinfectants to use, would be decided upon reviewing the trends of the environmental monitoring programme and periodic auditing of the cleaning and disinfection process rather than an edict to rotate two different disinfectants. Discussions with two MHRA inspectors confirmed that if environmental results/trends are under control, there would be no stipulated need to have achieved this using a rotational disinfectant programme.

The annex still mentions that “Monitoring should be undertaken regularly in order to show the effectiveness of the disinfectant program and to detect the development of resistant …”. In addition to the current version, it also now states “…and/or spore forming strains.” However, there is very little documented proof of acquired resistance to disinfectants at in-use concentrations rather than innate resistance and as a theory this has been largely discredited. Many facilities will routinely use a broad-spectrum disinfectant in rotation with a sporicide kept for intermittent or action point use. This is mainly due to the corrosive or aggressive nature of many sporicidal biocides rather than any concern over resistance. The more recent availability of highly effective cleanroom sporicides with no classified hazard may change this approach.

Disinfectant qualification
The current version of Annex 1 gives some clear guidance about the use of disinfectants and detergents. “Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised.” This is repeated in the draft Annex 1 but the exception for sterile dilutions is removed. It continues to state that “Disinfectants and detergents used in Grades A and B should be sterile prior to use.”

An additional requirement is that “Disinfectants should be shown to be effective for the duration of their in-use shelf life….” This will be relevant not only for dilutions made from concentrate but also RTU trigger sprays and presaturated wipes. Efficacy testing will be required for not only the unopened product at end of shelf life but also for the product during its in-use period. The expectation is that this work will be carried out on isolates and surfaces that are specific to the individual facility. The draft annex includes the phrase “….taking into consideration appropriate contact time and the manner in and surfaces on which they are utilized.”

This point is reinforced further:“Disinfectants should be shown to be effective when used on the specific facilities, equipment and processes that they are used in.” As well as standard lab testing on EN surfaces and with ATCC organisms, it is now clearly stated that work needs to be carried out on surfaces from the facility, if these are scratched and old, the test surfaces need to be scratched and old. They need to be effective against house isolates, these can change seasonally but will be shown by EM trends. Annex 1 now clarifies that “…if microorganisms are detected in a grade A or B zone, they should be identified to species level…Consideration should also be given to the identification of grade C and D contaminants, this requirement should be defined in the CCS.”

So what now?
The annex is still at a draft stage and there has been a call for a further consultation phase. The IWG met in September 2019 and it is likely that an amended draft will be sent out for another consultation phase in some form or another. However, there is a widely held view that the general direction of travel shown in the document will not change. It would be prudent to plan ahead with any disinfectant validation with these core principles in mind as it is likely that many will appear in the finished document.

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